title: The dopamine and cAMP regulated phosphoprotein, 32 kDa (DARPP-32) signaling pathway: a novel therapeutic target in traumatic brain injury.
abstract: Traumatic brain injury (TBI) causes persistent neurologic deficits. Current therapies, predominantly focused upon cortical and hippocampal cellular survival, have limited benefit on cognitive outcomes. Striatal damage is associated with deficits in executive function, learning, and memory. Dopamine and cAMP regulated phosphoprotein 32 (DARPP-32) is expressed within striatal medium spiny neurons and regulates striatal function. We found that controlled cortical impact injury in rats produces a chronic decrease in DARPP-32 phosphorylation at threonine-34 and an increase in protein phosphatase-1 activity. There is no effect of injury on threonine-75 phosphorylation or on DARPP-32 protein. Amantadine, shown to be efficacious in treating post-TBI cognitive deficits, given daily for two weeks is able to restore the loss of DARPP-32 phosphorylation and reduce protein phosphatase-1 activity. Amantadine also decreases the phosphorylation of threonine-75 consistent with activity as a partial N-methyl-D-aspartate (NMDA) receptor antagonist and partial dopamine agonist. These data demonstrate that targeting the DARPP-32 signaling cascade represents a promising novel therapeutic approach in the treatment of persistent deficits following a TBI.
authors.affiliation: Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Bales
authors.forename: Hong Q
authors.initials: HQ
authors.lastname: Yan
authors.forename: Xiecheng
authors.initials: X
authors.lastname: Ma
authors.forename: Youming
authors.initials: Y
authors.lastname: Li
authors.forename: Ranmal
authors.initials: R
authors.lastname: Samarasinghe
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
mesh_terms: D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D015259:Dopamine Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D000547:Amantadine